title: Cross talk between Wnt/β-catenin and Irf8 in leukemia progression and drug resistance.
abstract: Progression and disease relapse of chronic myeloid leukemia (CML) depends on leukemia-initiating cells (LIC) that resist treatment. Using mouse genetics and a BCR-ABL model of CML, we observed cross talk between Wnt/β-catenin signaling and the interferon-regulatory factor 8 (Irf8). In normal hematopoiesis, activation of β-catenin results in up-regulation of Irf8, which in turn limits oncogenic β-catenin functions. Self-renewal and myeloproliferation become dependent on β-catenin in Irf8-deficient animals that develop a CML-like disease. Combined Irf8 deletion and constitutive β-catenin activation result in progression of CML into fatal blast crisis, elevated leukemic potential of BCR-ABL-induced LICs, and Imatinib resistance. Interestingly, activated β-catenin enhances a preexisting Irf8-deficient gene signature, identifying β-catenin as an amplifier of progression-specific gene regulation in the shift of CML to blast crisis. Collectively, our data uncover Irf8 as a roadblock for β-catenin-driven leukemia and imply both factors as targets in combinatorial therapy.
authors.affiliation: Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Scheller
authors.forename: Jörg
authors.initials: J
authors.lastname: Schönheit
authors.forename: Karin
authors.initials: K
authors.lastname: Zimmermann
authors.forename: Ulf
authors.initials: U
authors.lastname: Leser
authors.forename: Frank
authors.initials: F
authors.lastname: Rosenbauer
authors.forename: Achim
authors.initials: A
authors.lastname: Leutz
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001752:Blast Crisis / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D016130:Immunophenotyping; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology*; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D058985:Side-Population Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D060449:Wnt Signaling Pathway; D000099185:Interferon Regulatory Factor-8
chemical_list: D001549:Benzamides; D000068877:Imatinib Mesylate; D050835:Interferon Regulatory Factors; D010879:Piperazines; D011743:Pyrimidines; D000099185:Interferon Regulatory Factor-8